Novel substituted indol-5-ols



United States Patent M 3,267,117 NOVEL SUBSTITUTED INDOL-S-OLS George Rodger Allen, Jr., Old Tappan, N..ll., and John Frank Poletto, Nanuet, N.Y., assignors to American Cyanamid Company, Stamford, Conn, a corporation of Maine No Drawing. Filed July 30, 1965, Ser. No. 476,184 2 Claims. (Cl. 260-326.16)

This application is a continuation-in-part of our copending application Serial No. 388,312, filed August 7, 1964; which in turn is a continuation-in-part of our application Serial No. 315,710, filed October 11, 1963, now abandoned.

This invention relates to new organic compounds and, more particularly, is concerned with novel indol-5-ols which may be represented by the following general formula:

wherein R is lower alkyl, R is lower alkyl or B-hydroxy lower alkyl, and R is lower alkyl. Suitable lower alkyl groups are those having up to about 6 carbon atoms. Suitable ,G-hydroxy lower alkyl groups contemplated by the present invention are those having up to about 6 carbon atoms such as, for example, fl-hydroxyethyl, B- hydroxy-n-propyl, fi-hydroxy-iso-propyl, ,B-hydroxy-mbutyl, etc.

The novel compounds of the present invention are obtainable as crystalline materials having characteristic melting points and absorption spectra. They are appreciably soluble in many organic solvents such as lower alkanols, acetone, ethyl acetate, and the like. They are, however, generally insoluble in water.

The novel indol-S-ols of the present invention are non-lethal psychoactive depressants and as such are usein] in the treatment of certain mental disorders. They may be administered either orally or parenterally and when so administered they have been found to exhibit central nervous system depressant action in amounts ranging from about 1.0 to about 50.0 milligrams per kilogram of body weight. It is indeed surprising that the known 2,6-dimethylind0l-5-ol exhibits no central nervous system depressant action, but rather is a central nervous system excitant.

A preferred dosage unit form is a tablet containing the novel indol-S-ol as the therapeutically active ingredient. For adults, such tablets should contain from 0.1 to 3.0 grams of the indol-S-ol. Of course, a tablet scored to be broken into dosage units or a number of tablets to be taken one at a time to constitute a dosage unit may also be employed. A second preferred dosage unit form is a capsule containing as the therapeutically active ingredient from 0.1 to 3.0 grams of the novel ind0l-5-ol. The capsule may be in either the hard or soft variety and may be made of any suitable capsule material which will disintegrate in the digestive tract. Examples of such encapsulating materials are gelatin and methyl cellulose.

Of course, the dosage unit form of the novel indol-S-ol of the present invention may also contain either inert or medically active material. For instance, when the dosage unit form is a tablet or granules there may also be present various binders, fillers, or solid diluents. There may also be present various medically active materials such as, for instance, aspirin, etc. When the dosage unit form is a capsule it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil; and

regardless of the dosage unit form, there may be present 3,267,117 Patented August 16, 1966 various flavors and excipients. Of course, any materials used in preparing the dosage unit forms must be pharmaceutically pure and substantially non-toxic in the amount employed.

The novel indol-S-ols of the present invention are also useful as intermediates in the preparation of the biologically active 3(a-carbamoyloxy-lower alkyl)-4,7-indoloquinones as is set forth in greater detail in our copending application Serial No. 388,312, filed August '7, 1964.

The novel indol-5-ols of the present invention may be readily prepared as set forth in the following reaction scheme:

M ii ii mccmoon. 112N112 mo=ono0ru (I) n no it NHRz 0 ii RX aac=cnconl+ U l 0 (III) N) nocom. no coin l I I R3 R2 I li 1 12 (V) VI nono- 1 14 1 34 I i 2 v11 vnr Thus, the indole system is generated by condensation of an alkyl-1,4-benzoquinone (IV) with an. alkyl 3-alkylaminocrotonate (III). This latter substance is available from the reaction of an alkylamine (II) with a fl-ketoester (I). The condensation of the benzoquinone (IV) and the aminocrotonate (III) usually gives a mixture of isomeric 5-hydroxyindole-3-canboxylic esters, e.g. (V) and (VI). These isomers may be separated by liquid-liquid partition chromatography on a neutral support, e.g.. diatomaceous silica. The alkyl S-hydroxy 1,2,6-trialkylindole-3-carboxylate (V) thus obtained may be decarbalkoxylated by any of several methods known to the art. The use of constant boiling hydrochloric acid is particularly advantageous for this transformation, inasmuch as this procedure converts the indole-3-canboxylic ester (V) into the novel 1,2,6-.trialkylindole-5-ols (VII) of this invention in one step.

Alternatively, the mixture of indole esters (V) and (VI) may be decarbalkoxylated with constant boiling hydrochloric acid, and the resulting mixture of 1,2,6-trialkylindol-S-ol (VII) and 1,2,7-trialkylindol-5-ol (VIII) may be separated by liquid-liquid partition chromatography on diatom aceous silica.

In the instances wherein R is B-hydroxy lower alkyl the preparation of the indol-S-ol is achieved by conversion of the indolecarboxylic ester (V) into the corresponding acid (V, R =H) by saponifioation and treatment of this latter material with a catalytic amount of mineral acid in a boiling lower alkanol.

The invention will be described in greater detail in conjunction with the following specific examples.

With mechanical stirring a stream of ethylamine is introduced into 98.5 g. (100 ml.) of ethyl acetoacetate for 3 hours. During the first hour cooling is required to combined filtrate and washings are concentrated to about 50 ml. volume and placed in the refrigerator for 16 hours. The solid is collected by filtration and washed with boiling light petroleum ether to give an additional 3.90 g. of

hold the temperature at 3540 C. where it is maintained 5 ggg g s gigg g gi g i g g l g g safizl throughout the reaction. Ether (200 ml.) is added, and Cr stals fi 198 c y g1 the water is separated. The ether is removed from the y Exam [as 8 organic phase and the residue is distilled under reduced 17 pressure to give a water white liquid, B.P. 20 mm. 116- In the manner described in Example 7, the products 118 C., n 1.4941, 104 g. 10 of Table II are obtained.

TABLE I1 HO COOCQH;

R1- N Rs Chromatography Ex. Starting Materials Products R1 Ra Ra .P., No. C.

Solvent System H.B.V. Vm/Vs 8 Ethyl-3-methyl- Toluquinone... Ethyl 5hydroxy-1,2,6-tri CH3 CH3 CH3 222-225 aminoerotonmethylindole-3-carate. boxylate. 9-.... Product of Ex- ..do Ethyl 5-hydroxy-2,G- CH3 C3111 CH3 HEDW (140:60z40z5)--. 2. 5 3.07 193. 5-

ample 2. dimethyl-l-propylin- 195. 0

dole3-earboxylate. 10--.. Product of Exdo Ethyl l-butyl-E-hydroxy- CH3 C4110 CH3 HEM1W (85:15:17:4)-.. 2. 5 2. 71 174.0-

ample 4. 2,6-di1nethylindolc-3- 176. 5

carboxylate. 11.... Product of Ex- .do Ethyl 1-isopropyl-5-hy- CH3 i-C3H1 CH3 HEM1W (80:20:17:4)-.. 1.4 3.08 201. 5-

ample 3. droxy-2,6-dimethyl- 203. 0

indole-3-carboxylate. 12.... Ethyl-3-arm'no- Ethyl-lA-ben- Ethyl G-ethyl-fi-hydroxy- CzHy, H CH3 HEMW(70:30:17:4) 3. 2 2.68 200-202 crotouate. zoquinone. 2-methylindole-3-carboxylate. 13.... Product of Ex- ...do Ethyl 1,6-diethyl-5-hy- C2115 CzH5 CH: HM (1Z1) 4. 5 2. 80 207-208 ample 1. droxy-2-methylindolescarboxylate. 14.... Product of Ex- Toluquinone.. Ethyl l,2-diethyl-5-hy- CH3 C Hg, C2I'I5 HEM1W (80:20:1724)... 1.3 3. 06 169.0 ample 6. droxy-6-methy1indole-3- 170. 5 carboxylate. 15.... Product of Exdo Ethyl 5-hydroxy-1-(B-hy- CH C2H4OH CH HEMW (60:40:15:6)... 2.4 3.00 195-196 ample 5. droxy'ethyD-lti-dimethylindole-iiearboxylate.

T Solvents: H=heptane, E=etl1yl acetate, M=n1ethanol, W=water, l\ I =2-methoxyethanol, D =dimethy1formamide; neutral suonorhdiatomaeeous S1 163.

Except where noted otherwise, all compounds were recrystallized from acetone-hexane.

E. Clemmensen, Ber., 47, (1914).

Examples 2-6 By the procedure described in Example 1 the compounds of Table I are obtained.

TAB LE I NHRr R3C=CHC O O C 11 50 indole-3-carboxylate and ethyl S-hydroxy-1,2,7trimethyl- Starting Materials Product v ExarInIple B.I., 0. (pressure) Ester Amine R; R;

Ethyl Acetoaeetate Propyl amine--... C3H1 CH 119--119.5 (14 mm). .do i-Propyl amine...- (0119 011-.-- CH3 106-106.5 (11 mm). Butyl amine 4 9 CH 129.5l3l.0 (14113111.) -.do Ethanolamine. CHZCII OH CH3 Decomposes. 6 Ethyl Propionylaeetate.-. Ethyl amine OgH5 C 11 118121 (14 mm.).

Example 7.Ethyl 1-ethyl-5-hydr0xy-2,6-dimethyl- 3-ind0le-carb0xylate A solution of 12.2 g. of (0.0855 mole) of ethyl-[i-ethylaminocrotonate in ml. of acetone is thoroughly swept with nitrogen and treated with 10.9 g. (0.085 mole) of toluquinone. The deep red solution is heated on the steam-bath for 2 hours, cooled in an ice bath and filtered to give a dark solid. This material is washed with cold acetone and dried to give 4.45 g. of gray crystals. The

indole-3-carboxylate is suspended in one liter of 20% hydrochloric acid solution. This suspension is heated at reflux temperature under nitrogen and with mechanical stirring for 2.5 hours; all solid dissolves. The pH of the solution is adjusted to 5.5-6.5 by addition of a concentrated sodium hydroxide solution. The cooled mixture is extracted with methylene chloride, and the dried (magnesium sulfate) extracts are evaporated to give a residue that crystallizes from methylene chloride-petroleum ether to furnish 9.8 g. (100%) of crystals. A 5.00 g.-sample of overnight. Filtration gives 108.7 g. of product as crystals, this material is subjected to partition chromatography on M.P. 118-120 C. A sample is obtained from acetonediatomaceous silica using a heptanezethyl acetate2methhexane as white needles, M.P. 121-123 C.; Amax 208, anolswater (80:20:17:4) system. Th fraction with 278, 294, 308 mu. 26,300; 8840; 6980; 4930); 298a. peak hold-back volume 2.4 (Vm/ Vs 3.12) is recrystallized 5 What is claimed is: from methylene chloride-petroleum ether to give in two 1. A compound of the formula: crops 3.233 g. of White crystals, M.P. 130.0-

Examples 17-22 1O Ri R: In the manner described in Example 16 the compounds of Table III are obtained.

TABLE III R1 N R3 Example Starting Material Product R1 R2 R3 M.P., C.- Number Produet of Example 7. l-ethyl2,6-dimethylindol-S-ol CH3 CzHs CH3 -92, -122 Product of Example 9 2,6-dimethyl-l-propylindol-fi-ol CH3 C3111 CHa 127-128 Product of Example 11.... 1-is0propyl-2,6-dimetl1y1ind01-5-ol CH3 i-C3H CH3 94-95 Product of Example 10.... 1-buty1-2,6-di1nethylindol-5-ol CH 04H CH 74-75 Product of Example 13...- 1,6-diethyl-Z-methylindol-S-ol. UzH5 C2H5 CH3 81-82 Product of Example 14.... 1,2-diethyl-6-methylindol-5-o1. CH C 115 C2115 88-90 a All compounds are recrystallized from methylene chloride-petroleum ether; they have Mnax 3.00-3.15 and no significant absorption in the carbonyl region; Arnax 209210 (E26,80029,400), 278-280 (e8460-9350), 295298 (e6910 7520), 308-310 m (54470-5490).

Example 23.1-(hydr0xyethyl)-2,6-dimethylind0l-5-0l wherein R is lower alkyl, R is B-hydroxy lower alkyl,

- 35 and R is lower alkyl.

A solution of 183.1 g. (0.66 mole) of ethyl 5-l1ydroxy- 3 1-hydroxyethyl-2,6-dimethyl-3-indolecar boxylate in 2000 l'm'hydroxyethyl)z6'dlmethyhndol's'ol' ml. of 2 N sodium hydroxide solution is heated at reflux temperature under nitrogen with mechanical stirring for 2 hours. The cooled solution is made acid to litmus paper 40 with hydrochloric acid solution. The moist precipitated solid, which has M.P. l59 C. (gas) and Amax 3.00, 3.80, 4.20, 608a, is suspended in 1500 ml. of methanol. This solution is warmed of the steam bath. Before the solution reaches boiling, copious evolution of gas bubbles is noted. Once boiling temperature is attained all solid has dissolved; this solution is heated at its boiling point for 1 hour and then concentrated to 700 ml. Water (1300 m1.) is added, and the solution is chilled References Cited by the Examiner UNITED STATES PATENTS 2,787,551 4/1957 Bell et val. 260-319 XR OTHER REFERENCES r Beer et al., J our. Chem. Soc., 1951, pages 2029-2032. a ALEX MAZEL, Primary Examiner.

HENRY R. JILES, Examiner.

MARY U. OBRIEN, Assistant Examiner. 

1. A COMPOUND OF THE FORMULA: 